Poly-4-hydroxybutyrate (P4HB) and copolymers thereof can be produced using transgenic fermentation methods, see, for example, U.S. Pat. No. 6,548,569 to Williams et al., and are produced commercially, for example, by Tepha, Inc. (Lexington, Mass.). Poly-4-hydroxybutyrate (P4HB, TephaFLEX® biomaterial) is a strong, pliable thermoplastic polyester that, despite its biosynthetic route, has a relatively simple structure. Upon implantation, P4HB hydrolyzes to its monomer, and the monomer is metabolized via the Krebs cycle to carbon dioxide and water.
The polymer belongs to a larger class of materials called polyhydroxyalkanoates that are produced by numerous microorganisms (see, for example, Steinbüchel A., et al. Diversity of Bacterial Polyhydroxyalkanoic Acids, FEMS Microbial. Lett. 128:219-228 (1995)). In nature these polyesters are produced as storage granules inside cells, and serve to regulate energy metabolism. They are also of commercial interest because of their thermoplastic properties, and relative ease of production.
Chemical synthesis of P4HB has been attempted, but it has been impossible to produce the polymer with a sufficiently high molecular weight that is necessary for most applications (see Hori, Y., et al., Polymer 36:4703-4705 (1995) and Houk, K. N., et al., J. Org. Chem., 2008, 73 (7), 2674-2678).
P4HB is a strong but extensible polymer similar to low density polypropylene, and should not be confused with poly-3-hydroxybutyrate, often referred to as “PHB” or “P3HB”. Unlike P4HB, PHB is a brittle polymer that has properties resembling polystyrene. For example, PHB has a melting point and glass transition temperature of approximately 80° C. and 1° C., respectively, and an elongation to break of about 3%, whereas P4HB has a melting point of 60° C., a glass transition temperature of approximately −51° C., and elongation to break of around 1,000%. Thus, PHB and P4HB possess substantially different thermal and physical properties.
U.S. Pat. Nos. 6,245,537, 6,623,748, 7,244,442, and 8,231,889 describe methods of making polyhydroxyalkanoates with little to no endotoxin, which are suitable for medical applications. U.S. Pat. Nos. 6,548,569, 6,838,493, 6,867,247, 7,268,205, 7,179,883, 7,268,205, 7,553,923, 7,618,448 and 7,641,825 and WO 2012/064526 describe use of polyhydroxyalkanoates to make medical devices. Copolymers of P4HB include 4-hydroxybutyrate copolymerized with 3-hydroxybutyrate or glycolic acid (U.S. Pat. No. 8,039,237 to Martin and Skraly, U.S. Pat. No. 6,316,262 to Huisman et al., and U.S. Pat. No. 6,323,010 to Skraly et al.). Methods to control molecular weight of polyhydroxyalkanoate polymers have been disclosed by U.S. Pat. No. 5,811,272 to Snell et al.
Polyhydroxyalkanoates with controlled degradation and degradation in vivo of less than one year are disclosed by U.S. Pat. Nos. 6,548,569, 6,610,764, 6,828,357, 6,867,248, and 6,878,758 to Williams et al. and WO 99/32536 to Martin et al. Applications of P4HB have been reviewed in Williams, S. F., et al., Polyesters, III, 4:91-127 (2002), and by Martin, D. et al. Medical Applications of Poly-4-hydroxybutyrate: A Strong Flexible Absorbable Biomaterial, Biochem. Eng. J. 16:97-105 (2003). Medical devices and applications of P4HB have also been disclosed by WO 00/56376 to Williams et al., U.S. Pat. No. 8,034,270 to Martin et al., WO 2011/119743 to Martin et al., U.S. Pat. No. 8,016,883 to Coleman et al., U.S. Pat. No. 8,287,909 to Martin et al., and WO 2011/159784 to Cahil et al. Several patents including U.S. Pat. Nos. 6,555,123, 6,585,994, and 7,025,980 describe the use of polyhydroxyalkanoates in tissue repair and engineering.
WO 00/56376 to Williams et al. discloses open cell P4HB foams produced by thermal phase separation. The foams were produced by solidifying a cast film of P4HB in dioxane at a temperature below the melting point of dioxane, and evaporating the solvent from this solid material at low pressure. WO 05/020825 to Terenghi et al. discloses an alternative particulate leaching method to form P4HB open cell foams. In this method, P4HB was dissolved in dioxane, mixed with salt particles, pressed into a sheet, frozen at −26° C., lyophilized to remove the solvent, and then the particulate was leached from the sample with water to yield an open cell P4HB foam. Both methods yield an open cell architecture, not a closed cell system, and contain residual solvent.
There currently exists a need for surgical structures including closed cell foams with improved performance. These structures can be used, for example, in both soft and hard tissue repair, to heal wounds, control bleeding, protect wound beds, prevent infection, apply pressure to a tissue surface or structure, prevent movement of bodily fluids, absorb fluids, deliver bioactive agents, reinforce tissue structures, separate tissues, and regenerate tissues.
A number of absorbable materials have been used to produce closed cell foams. For example, U.S. Pat. No. 5,134,171 to Hammel et al. discloses closed cell foams produced from polylactic acid, polyglycolic acid, copolymers of lactic and glycolic acids, and these monomers co-polymerized with various hydroxy acids. U.S. Pat. No. 5,210,108 to Spinu et al. discloses closed cell foams prepared from star-shaped absorbable polymers.
Although polymers and copolymers of lactic and glycolic acids are used to produce various medical devices, these materials do not have ideal properties for many procedures and applications. For example, glycolic acid containing polymers are very sensitive to moisture, release very acidic degradation products that can cause inflammatory reactions, and degrade quickly when implanted in the body.
It is an object of the present invention to provide methods to produce substantially closed cell foams including poly-4-hydroxybutyrate and copolymers thereof with an open cell content of generally less than 50%, and more preferably with an open cell content of less than 20%.
It is a further object of the present invention to provide methods to produce substantially closed cell foams including poly-4-hydroxybutyrate and copolymers thereof that have densities of less than 0.75 g/cm3.
It is another object of the present invention to provide methods to produce substantially closed cell foams wherein the maximum diameter of the cells is less than 5 mm.
It is still a further object of the invention to provide formulations for preparing substantially closed cell foams including poly-4-hydroxybutyrate and copolymers thereof that in addition to a blowing agent include one or more of a plasticizer, surfactant, or nucleant.
It is still a further object of the invention to provide continuous processes to produce substantially closed cell foams including poly-4-hydroxybutyrate and copolymers thereof by melt-foaming with an open cell content of generally less than 50%, and processes to form medical devices from these closed cell foams.
It is still yet another object of the invention to provide substantially closed cell foams of poly-4-hydroxybutyrate and copolymers thereof, which are biocompatible and can be used for medical applications, for example, as devices for use in both soft and hard tissue repair, to heal wounds, control bleeding, protect wound beds, prevent infection, apply pressure to a tissue surface or structure, prevent movement of bodily fluids, absorb fluids, deliver bioactive agents, reinforce tissue structures, separate tissues, prevent adhesions, and regenerate tissues, and including wound dressings, tapes, patches, seals, scaffolds, hemostats, pledgets, wound closure devices, compression bandages, orthopedic foams, surgical foams, and orthodontic devices.
It is therefore an object of the invention to provide continuous processes for production of substantially closed cell foams including poly-4-hydroxybutyrate and copolymers thereof, which can be incorporated into or formed into medical products with excellent physical and mechanical properties for medical applications.